Hydrogel string medical device

ABSTRACT

A hydrogel string that is useful as a medical device and a method for forming a hydrogel string that utilizes a delivery device in which gelation of a prepolymer is initiated to form a hydrogel, which is then extruded from the device as the hydrogel string.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional ApplicationSer. No. 60/457,735, filed on Mar. 25, 2003.

BACKGROUND OF THE INVENTION

[0002] The invention relates to a hydrogel string useful as a medicaldevice and to a method for forming a hydrogel string. The methodutilizes a device in which a prepolymer composition is brought intocontact with a gelation initiator to form a hydrogel, which is thenextruded from the device as the hydrogel string.

[0003] Hydrogels have been shown to be useful for a number of biomedicalapplications. For example, there are many instances in which anappropriate hydrogel biomaterial has been shown to be useful in repairof tissues and in augmentation of tissues, such as repair of defects andconditions in a tissue caused by disease, injury, or aging, repair ofcongenital defects and conditions in a tissue, and augmentation oftissues to provide a desirable functional, reconstructive, or cosmeticchange. Bulking of the lower esophageal sphincter has been used fortreatment of gastroesophageal reflux disease (GERD). Vesicoureteralreflux can be treated by endoscopic injection of a bulking agent in thesubmucosal space. Some types of incontinence can be treated by injectionof a bulking agent into the submucosa of the urethra, in order to “beefup” the area and improve muscle tone. Spinal disc replacement oraugmentation is another application where the use of hydrogels has beenexplored.

[0004] Another application for an appropriate hydrogel biomaterial istissue embolization. Hydrogel embolic agents are useful for a variety ofbioapplications, such as occluding blood vessels, occluding other bodylumens such as fallopian tubes, filling aneurysm sacs, as arterialsealants, and as puncture sealants. Embolization of blood vessels isperformed for a number of reasons, e.g. to reduce blood flow to andencourage atrophy of tumors, such as in the liver, to reduce blood flowand induce atrophy of uterine fibroids, for treatment of vascularmalformations, such as arteriovenous malformations (AVMs) andarteriovenous fistulas (AVFs), to seal endoleaks into aneurysm sacs, tostop uncontrolled bleeding, or to slow bleeding prior to surgery.

[0005] Hydrogels have also been developed and used for drug delivery.

[0006] Hydrogel biomaterials can be preformed, such as hydrogel discsfor drug delivery, or hydrogel microspheres for embolization. Hydrogelscan also be formed in situ- at the site of embolization, for example.Each form has its advantages and disadvantages. Solid, preformedarticles can be difficult to administer; larger articles can requireinvasive surgery and smaller articles can migrate after implantation.For example, solid particles and microspheres are generally unsuitablefor filling aneurysms, particularly wide-necked aneurysms, due tomigration of the particles or microspheres out of the sac.

[0007] Liquid, in situ formed materials can be flushed from the siteduring implantation. Another disadvantage is that the liquid may notform a cohesive solid mass, and bits of the hydrogel may be sloughed offover time.

[0008] Preformed polymeric strings have been proposed for use asbiomaterials. U.S. Pat. No. 6,312,421 to Boock proposes preformedstrings that are placed into a catheter for implantation. The stringsare available in a set length, which reduces the flexibility of theiruse.

[0009] It would seem, therefore, that a hydrogel string that is formedat the time of delivery would be useful for many biomedicalapplications. The string would be available in the desired length, sinceit would be formed at the time of use.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 is a schematic of one embodiment of the hydrogel stringdelivery device.

[0011]FIG. 2 is a schematic of the distal tip of one embodiment of thehydrogel string delivery device, showing the mixing chamber and theextruded hydrogel string.

SUMMARY OF THE INVENTION

[0012] A hydrogel string that is useful as a medical device and a methodfor forming a hydrogel string that utilizes a delivery device in whichgelation of a prepolymer is initiated to form a hydrogel, which is thenextruded from the device as the hydrogel string.

DETAILED DESCRIPTION OF THE INVENTION

[0013] “Hydrogel” refers to a material having an aqueous phase with aninterlaced polymeric component, with at least 10% to 90% of its weightas water.

[0014] “Macromer” means a crosslinkable macromonomer.

[0015] “Microcatheter” means a catheter having a distal tip size ofabout 4 French or smaller.

[0016] “Prepolymer” means a macromer or polymer composition that forms ahydrogel upon exposure to some initiation event.

[0017] In one aspect, the invention is a hydrogel string that is usefulas a medical device. In another aspect, the invention is a method forforming a hydrogel string. The method utilizes a delivery device inwhich the hydrogel is formed within the device and extruded from thedevice at the intended site. The hydrogel can be formed in any manner,generally from a prepolymer that is brought into contact with aninitiator within the device. The prepolymer component(s) are fed to thedevice from syringes or other reservoirs and the string can be formedand extruded having a length as long as desired. In one embodiment, thestring is formed by bringing together two liquid components that form ahydrogel when combined in the device, and then extruding or pushing thestring out of the device. In another embodiment, the string can beformed by having an initiator within the device, wherein the prepolymercontacts the initiator, the hydrogel forms, and is then extruded fromthe device. For example, the initiator could be part of the tip of acatheter.

[0018] In the preferred embodiment, the method involves bringingtogether two liquid components within a dual lumen catheter, having amixing tip on the end. A variety of configurations of the two liquidcomponents is possible. In one embodiment, the two liquid components mayeach contain prepolymer, whereupon the prepolymers form the hydrogelwhen mixed. In another embodiment, the two liquid components may eachcontain prepolymers and one or both components may contain acrosslinking initiator. In another embodiment, the prepolymer may becontained in only one component, while one or both components contain acrosslinking initiator. Or, the prepolymer may be in one component,while the initiator is in the other component. In any event, a hydrogelis formed when the components mix in the mixing tip.

[0019] The mixing and hydrogel formation is achieved within the lumen ofthe delivery catheter (or within the needle of a syringe). The hydrogelexits the catheter distal end as a string of fully or partiallycrosslinked hydrogel.

[0020] The Hydrogel Forming Components

[0021] The hydrogel string is formed from one or more prepolymers thatcan gel to form a hydrogel. Examples include hydrogels formed frommacromers, as described in WO 01/68720 to BioCure, Inc. and U.S. Pat.No. 5,410,016 to Hubbell et al.

[0022] Gelation of the prepolymer can be via a number of mechanisms,such as physical crosslinking or chemical crosslinking. Physicalcrosslinking includes, but is not limited to, complexation, hydrogenbonding, desolvation, Van der wals interactions, and ionic bonding.Chemical crosslinking can be accomplished by a number of meansincluding, but not limited to, chain reaction (addition) polymerization,step reaction (condensation) polymerization and other methods ofincreasing the molecular weight of polymers/oligomers to very highmolecular weights. Chain reaction polymerization includes, but is notlimited to, free radical polymerization (thermal, photo, redox, atomtransfer polymerization, etc.), cationic polymerization (includingonium), anionic polymerization (including group transferpolymerization), certain types of coordination polymerization, certaintypes of ring opening and metathesis polymerizations, etc. Step reactionpolymerizations include all polymerizations which follow step growthkinetics including but not limited to reactions of nucleophiles withelectrophiles, certain types of coordination polymerization, certaintypes of ring opening and metathesis polymerizations, etc. Other methodsof increasing molecular weight of polymers/oligomers include but are notlimited to polyelectrolyte formation, grafting, ionic crosslinking, etc.

[0023] Various crosslinkable groups are known to those skilled in theart and can be used, according to what type of crosslinking is desired.For example, hydrogels can be formed by the ionic interaction ofdivalent cationic metal ions (such as Ca⁺² and Mg⁺²) with ionicpolysaccharides such as alginates, xanthan gums, natural gum, agar,agarose, carrageenan, fucoidan, furcellaran, laminaran, hypnea,eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth, locustbeam gum, arabinogalactan, pectin, and amylopectin. Multifunctionalcationic polymers, such as poly(l-lysine), poly(allylamine),poly(ethyleneimine), poly(guanidine), poly(vinyl amine), which contain aplurality of amine functionalities along the backbone, may be used tofurther induce ionic crosslinks.

[0024] Hydrophobic interactions are often able to induce physicalentanglement, especially in polymers, that induces increases inviscosity, precipitation, or gelation of polymeric solutions. Block andgraft copolymers of water soluble and insoluble polymers exhibit sucheffects, for example, poly(oxyethylene)-poly(oxypropylene) blockcopolymers, copolymers of poly(oxyethylene) with poly(styrene),poly(caprolactone), poly(butadiene), etc.

[0025] Other means for gelation also may be advantageously used withprepolymers that contain groups that demonstrate activity towardsfunctional groups such as amines, imines, thiols, carboxyls,isocyanates, urethanes, amides, thiocyanates, hydroxyls, etc.

[0026] Desirable crosslinkable groups include (meth)acrylamide,(meth)acrylate, styryl, vinyl ester, vinyl ketone, vinyl ethers, etc.Particularly desirable are ethylenically unsaturated functional groups.

[0027] The method can be used to form a hydrogel string from anyprepolymer system wherein a hydrogel can be formed by contacting theprepolymer with an initiator. For example, dual polymer systems such asthat disclosed in U.S. Pat. No. 6,534,591 to Rhee et al. can be used.

[0028] The hydrogel can be formed from one or more macromers thatinclude a hydrophilic or water soluble region and one or morecrosslinkable regions. The macromers may also include other elementssuch as one or more degradable or biodegradable regions. A variety offactors-primarily the desired characteristics of the formedhydrogel—determines the most appropriate macromers to use. Many macromersystems that form biocompatible hydrogels can be used.

[0029] Macromers can be constructed from a number of hydrophilicpolymers, such as, but not limited to, polyvinyl alcohols (PVA),polyethylene glycols (PEG), polyvinyl pyrrolidone (PVP), polyalkylhydroxy acrylates and methacrylates (e.g. hydroxyethyl methacrylate(HEMA), hydroxybutyl methacrylate (HBMA), and dimethylaminoethylmethacrylate (DMEMA)), polysaccharides (e.g. cellulose, dextran),polyacrylic acid, polyamino acids (e.g. polylysine, polyethylmine, PAMAMdendrimers), polyacrylamides (e.g. polydimethylacrylamid-co-HEMA,polydimethylacrylamid-co-HBMA, polydimethylacrylamid-co-DMEMA). Themacromers can be linear or can have a branched, hyperbranched, ordendritic structure.

[0030] Macromers suitable for use in the compositions described hereinare disclosed in WO 01/68720 to BioCure, Inc. Other suitable macromersinclude those disclosed in U.S. Pat. No. 5,410,016 to Hubbell et al.,U.S. Pat. No. 4,938,763 to Dunn et al., U.S. Pat. No. 5,100,992 and U.S.Pat. No. 4,826,945 to Cohn et al., U.S. Pat. No. 4,741,872 and U.S. Pat.No. 5,160,745 to De Luca et al, and U.S. Pat. No. 4,511,478 to Nowinskiet al.

[0031] In a preferred embodiment, the macromers are those described inWO 01/68720 to BioCure, Inc. These macromers have a PVA backbone and atleast two pendant chains containing ethylenically unsaturated groupsthat can be crosslinked. The crosslinkers are desirably present in anamount of from approximately 0.01 to 10 milliequivalents of crosslinkerper gram of backbone (meq/g), more desirably about 0.05 to 1.5 meq/g.

[0032] The ethylenically unsaturated groups are crosslinked using a twopart redox system. One part of the system contains a reducing agent suchas a ferrous salt. Various ferrous salts can be used, such as, forexample, ferrous gluconate dihydrate, ferrous lactate dihydrate, orferrous acetate. The other half of the system contains an oxidizingagent such as hydrogen peroxide.

[0033] Other reducing agents can be used, such as, but not limited to,cuprous salts, cerous salts, cobaltous salts, permanganate, andmanganous salts. Ascorbate, for example, can be used as a coreductant torecycle the reductant and reduce the amount needed. This can reduce thetoxicity of a ferrous based system. Other oxidizing agents that can beused include, but are not limited to, t-butyl hydroperoxide, t-butylperoxide, benzoyl peroxide, cumyl peroxide, etc.

[0034] The Delivery Device

[0035] The hydrogel string is formed within and delivered from adelivery device. Desirably, the device includes or is connected to areservoir for the prepolymer, and includes the initiator. The deviceincludes a mixing tip, or gelation tip, where the prepolymer contactsthe initiator and forms the hydrogel. The device also includes a way toextrude the formed hydrogel out of the device. The preferred embodimentof the delivery device is a catheter. The catheter can be multilumen,especially if the initiator is provided via a second liquid.

[0036] In a preferred embodiment, a catheter having at least two lumensis employed in the method for forming the hydrogel string. Aside-by-side dual lumen catheter can be used although a coaxial catheteris preferred. The distal portion of the catheter includes a gelationchamber of sufficient length for the two solutions to mix and form thehydrogel string. Preferably, one of the lumens or catheters is slidablewithin the mixing chamber, so that the length of the gelation chambercan be changed.

[0037] In one embodiment, the catheter is a coaxial dual lumen catheter,having a first, or outer, catheter and a second, or inner, catheter. Thesecond catheter is positioned inside the first catheter to form acoaxial dual lumen catheter. The catheters are desirably used with amanifold, which provides for connection between the catheters andreservoirs that the two solutions are delivered from—such as syringes.

[0038] The device can further include a syringe holder, into which thesyringes can be placed so that delivery of the two solutions can besynchronized. A guidewire can be used, if desired, to aid in placementof the catheters.

[0039] In one embodiment, illustrated by FIG. 1, the device 10 includesfirst catheter 16, which can be attached to the manifold 20 at itsproximal end 18 via a luer adaptor 19, for example.

[0040] The manifold 20 includes a syringe adaptor 22 which providesconnection (via a luer lock for example) between the interior space 26of the manifold 20 (which leads into the first, outer catheter) and asyringe (not shown) for the first solution. The second, inner, catheter30 is sized so that it can be slid inside the first catheter 16.

[0041] Furthermore, the second catheter should be sized to allow flow ofa solution through the first catheter when the second catheter is inplace. In other words, the second catheter should not fit too tightlywithin the first catheter.

[0042] The manifold 20 includes a second adaptor 34 to receive thesecond catheter 30. This can be a Tuohy-Borst adaptor, through which thesecond catheter can be inserted. The second catheter 30 is then pushedthrough the manifold and into and through the first catheter 16.Accordingly, the second solution delivered through the second catheter30 does not contact the first solution delivered through the firstcatheter 16. A syringe (not shown) is fastened to the second catheter 30for delivery of the second solution.

[0043] As shown in FIG. 2, second catheter 30 terminates some distancebefore first catheter 16 so that gelation chamber 36 is formed at thedistal end of first catheter 16. As the two solutions are combined inthe gelation chamber 36, they form the hydrogel string 40.

[0044] If desired, the first and second syringes are retained within asyringe holder (not shown) which allows synchronized delivery of the twosolutions. The manifold would desirably be designed so that the syringesare aligned.

[0045] For placement of the delivery device within the vasculature atthe intended application site, a guidewire (not shown) can be used.

[0046] The first catheter can be a commercially available catheter, suchas a FasTracker 325 or Tracker 18 microcatheter. It should be ofappropriate size to access the intended site of application. The outerdiameter of the first catheter therefore can be of any size, so long asit is appropriate for the application. The presently disclosed device isparticularly applicable for neurovascular applications or site selectiveapplications which, in some cases, require microcatheters down to 1.6 Fror smaller. The practical upper limit to catheter size is about 8 Fr.

[0047] In one example, the first catheter can be a Tracker 18, having aninner diameter of 0.021 inches. The second catheter can have an outerdiameter of 0.012 inches, and an inner diameter of 0.009 inches. Thespace between the first catheter's inner diameter and the secondcatheter's outer diameter can vary in size. The second catheter may beas small-as about 0.7 Fr.

[0048] The first catheter can be made of standard catheter materials,typically a polymer such as, for example, polyurethane, polyethylene,silicone, or nylon. The second microcatheter can be made of a polymerbut is desirably made of metal such as stainless steel or a binarynickel titanium alloy (nitinol). The second catheter can also be formedfrom standard catheter plastics but for use as a microcatheter isdesirably formed from a metal, such as platinum, a platinum alloy, anickel alloy, a titanium alloy, and some types of stainless steel (suchas 316L stainless steel). Desirably, a binary nickel titanium alloy(nitinol) is used. Some plastics such as polyimide, polyethylene,polyurethane, and PTFE may be useful. The requirements for thefabrication material will depend upon the desired characteristics of themicrocatheter, such as flexibility and strength, and the designparameters such as length and diameter. Desirably, medical gradesuperelastic nitinol is used.

[0049] The Method

[0050] The method for forming the hydrogel string is described withrespect to filling an aneurysm but the method is applicable to a varietyof biomedical applications. For example, the method and string can beused for repair of defects and conditions in a tissue caused by disease,injury, or aging, repair of congenital defects and conditions in atissue, and augmentation of tissues to provide a desirable functional,reconstructive, or cosmetic change. Examples include bulking of thelower esophageal sphincter for treatment of gastroesophageal refluxdisease (GERD), endoscopic injection of a bulking agent in thesubmucosal space to treat vesicoureteral reflux, treatment ofincontinence by injection of a bulking agent into the submucosa of theurethra, in order to “beef up” the area and improve muscle tone, andreplacement or augmentation of a spinal disc.

[0051] A variety of configurations of the two liquid components ispossible. In one embodiment, the two liquid components may each containprepolymer, whereupon the prepolymers form the hydrogel when mixed. Inanother embodiment, the two liquid components may each containprepolymers and one or both components may contain a crosslinkinginitiator. In another embodiment, the prepolymer may be contained inonly one component, while one or both components contain a crosslinkinginitiator. Or, the prepolymer may be in one component, while theinitiator is in the other component.

[0052] In a preferred embodiment of the method, the coaxial dual lumenmicrocatheter described above is used. Since the inner diameter of theinner catheter is so small, the viscosity of the solution deliveredthrough the inner catheter must be low. Solution containing macromer isdelivered through the first (outer) catheter; and initiator solution isdelivered through the second (inner) catheter. The initiator can beeither reductant or oxidant and the other of the pair is delivered withthe macromer. Liquid contrast agent can be contained in both solutions.

[0053] Using the microcatheter described above, the first (outer)catheter is positioned at the administration site, desirably using aguidewire. The second (inner) catheter is threaded through the firstcatheter (first removing the guidewire if one has been used). The firstand second catheters are connected to syringes or other dispensersholding the two solutions (as described above). The catheters may bepart of a delivery device including a manifold and syringe holder, ifdesired. The method then involves delivering the two solutions which gelin the catheter gelling chamber.

[0054] The nature of the string 40 in the gelation chamber 36 changesthrough the length of the gelation chamber 36. At the proximal end ofthe chamber, the solutions are first coming into contact and begin tomix. Initiation of gelation begins and the string begins to form. Asshown in FIG. 2, the composition is liquid at the proximal end andgelled at the distal end. Further injection of solutions into thecatheters force the string out of the distal tip of the catheter andinto the aneurysm, for example.

[0055] Desirably, the inner catheter is slidable within the outercatheter. If the operator wants to inject a less gelled composition intothe aneurysm, he can slide the inner catheter towards the distal end ofthe gelation chamber, which means the composition exiting the catheterwill be less solid. This may be desirable, for example, in order to fillin the spaces.

[0056] The method can deliver a composition ranging from a distinctsolid string to a semi-solid near liquid.

[0057] The gelation time of the compositions can be varied from about0.5 seconds to as long as 10 minutes, and longer if desired. Thegelation time will generally be affected by, and can be modified bychanging at least the following variables: the initiator system,crosslinker density, macromer molecular weight, macromer concentration(solids content), and type of crosslinker. A higher crosslinker densitywill provide faster gelation time; a lower molecular weight will providea slower gelation time. A higher solids content will provide fastergelation time. For redox systems the gelation time can be designed byvarying the concentrations of the redox components. Higher reductant andhigher oxidant will provide faster gelation, higher buffer concentrationand lower pH will provide faster gelation.

[0058] The firmness of the formed hydrogel will be determined in part bythe hydrophilic/hydrophobic balance, where a higher hydrophobic percentprovides a firmer hydrogel. The firmness will also be determined by thecrosslinker density (higher density provides a firmer hydrogel), themacromer molecular weight (lower MW provides a firmer hydrogel), and thelength of the crosslinker (a shorter crosslinker provides a firmerhydrogel).

[0059] The swelling of the hydrogel is inversely proportional to thecrosslinker density. Generally, no or minimal swelling is desired,desirably less than about 10 percent.

[0060] Elasticity of the formed hydrogel can be increased by increasingthe size of the backbone between crosslinks and decreasing thecrosslinker density. Incomplete crosslinking will also provide a moreelastic hydrogel. Preferably the elasticity of the hydrogelsubstantially matches the elasticity of the tissue to which thecomposition is to administered.

[0061] Contrast Agents

[0062] It may be desirable to include a contrast agent in the hydrogelstring. A contrast agent is a biocompatible (non-toxic) material capableof being monitored by, for example, radiography. The contrast agent canbe water soluble or water insoluble. Examples of water soluble contrastagents include metrizamide, iopamidol, iothalamate sodium, iodomidesodium, and meglumine. Iodinated liquid contrast agents includeOmnipaque®, Visipaque®, and Hypaque-76®. Examples of water insolublecontrast agents are tantalum, tantalum oxide, barium sulfate, gold,tungsten, and platinum. These are commonly available as particlespreferably having a size of about 10 μm or less.

[0063] The contrast agent can be added to one or both of the solutionsprior to administration. Both solid and liquid contrast agents can besimply mixed with one or both solutions. Liquid contrast agent can bemixed at a concentration of about 10 to 80 volume percent, moredesirably about 20 to 50 volume percent. Solid contrast agents aredesirably added in an amount of about 10 to 40 weight percent, morepreferably about 20 to 40 weight percent.

[0064] Active Agents

[0065] An effective amount of one or more biologically active agents canbe incorporated into the hydrogel string simply by including the agentin one or both solutions. It may be desirable to deliver the activeagent from the formed hydrogel. Biologically active agents that it maybe desirable to deliver include prophylactic, therapeutic, anddiagnostic agents including organic and inorganic molecules and cells(collectively referred to herein as an “active agent” or “drug”). A widevariety of active agents can be incorporated into the hydrogel. Releaseof the incorporated additive from the hydrogel is achieved by diffusionof the agent from the hydrogel, degradation of the hydrogel, and/ordegradation of a chemical link coupling the agent to the polymer. Inthis context, an “effective amount” refers to the amount of active agentrequired to obtain the desired effect.

[0066] Examples of active agents that can be incorporated include, butare not limited to, anti-angiogenic agents, chemotherapeutic agents,radiation delivery devices, such as radioactive seeds for brachytherapy,and gene therapy compositions.

[0067] Chemotherapeutic agents that can be incorporated include watersoluble chemotherapeutic agents, such as cisplatin (platinol),doxorubicin (adriamycin, rubex), or mitomycin C (mutamycin). Otherchemotherapeutic agents include iodinated fatty acid ethyl esters ofpoppy seed oil, such as lipiodol.

[0068] Cells can be incorporated into the compositions, including cellsto encourage tissue growth or cells to secrete a desired active agent.For example, cells that can be incorporated include fibroblasts,endothelial cells, muscle cells, stem cells, etc. Cells can be modifiedto secrete active agents such as growth factors.

[0069] Active agents can be incorporated into the compositions simply bymixing the agent with one or both solutions. The active agent will thenbe entrapped in the hydrogel string. The active agent can be in compoundform or can be in the form of degradable or nondegradable nano ormicrospheres. It some cases, it may be possible and desirable to attachthe active agent to the macromer. The active agent may be released fromthe macromer or hydrogel over time or in response to an environmentalcondition.

[0070] Other Additives

[0071] It may be desirable to include a peroxide stabilizer in redoxinitiated systems. Examples of peroxide stabilizers are Dequest®products from Solutia Inc., such as for example Dequest® 2010 andDequest® 2060S. These are phosphonates and chelants that offerstabilization of peroxide systems. Dequest® 2060S is diethylenetriaminepenta(methylene phosphonic acid). These can be added in amounts asrecommended by the manufacturer.

[0072] It may be desirable to include fillers in the compositions, suchas fillers that leach out of the formed hydrogel over a period of timeand cause the hydrogel to become porous. Such may be desirable, forexample, where the composition is used for chemoembolization and it maybe desirable to administer a follow up dose of chemoactive agent.Appropriate fillers include calcium salts, for example.

[0073] The examples below serves to further illustrate the invention, toprovide those of ordinary skill in the art with a complete disclosureand description of how the compounds, compositions, articles, devices,and/or methods claimed herein are made and evaluated, and is notintended to limit the scope of the invention. In the examples, unlessexpressly stated otherwise, amounts and percentages are by weight,temperature is in degrees Celsius or is at ambient temperature, andpressure is at or near atmospheric. The examples are not intended torestrict the scope of the invention.

EXAMPLE 1

[0074] Two prepolymer solutions were formulated as follows. Eachsolution was individually weighed or dispensed into a 20 mlscintillation vial furnished with a magnetic stirrer bar then stirreduntil homogeneous. The solutions were then allowed to stand to allow anyresulting air bubbles to dissipate. Part A: 30% Acrylamidefunctionalized PVA macromer 2.33 g 50% 2-acrylamido-2-methylpropanesuiphonate, 0.60 g sodium salt (pH 8) Omnipaque 350 5.00 g 415 mMHydrogen peroxide 500 uL Deionized water 1.57 g

[0075] Part B: 50% 2-acrylamido-2-methylpropane sulphonate, 2.00 gsodium salt (pH 8) Omnipaque 350 5.00 g  83 mM Fe(II) lactate 1.50 g 415mM Ascorbic acid 0.20 g Deionized water 1.30 g

[0076] The prepolymer solutions Part A and Part B were delivered via acoaxial microcatheter system. A Touy-Borst Y-connect was attached to aFasTracker 325 microcatheter (Boston Scientific, Target; Length=125 cm)then flushed with saline. A nitinol catheter (length=165 cm, o.d.=0.012inches) with a spiral cut tip was preflushed with saline and insertedinto the microcatheter via the Y-connector. Once the tip of the nitinolcatheter was approximately 10 cm behind the tip of the microcatheter itwas secured in place with the Y-connector.

[0077] Solution Part A was drawn up in a mL Luer-Lok syringe thenattached to the Y-connector. The thread on the Y-connector (used to lockthe nitinol catheter in place) was loosened. The Y-connector was thenback flushed with solution Part A to replace the saline (which wasexpelled via the loosened top thread of the Y-connector). Once thesaline was exchanged, the thread on the Y-connector was retightened andinjection of solution Part A was continued to allow flushing of themicrocatheter. Once this was completed the syringe was removed andrefilled. The syringe was attached to a hand torque syringe deliverydevice then reattached to the Y-connect being careful to avoid theformation of air bubbles.

[0078] The nitinol catheter was flushed with saline using a Luer-Loksyringe. Solution Part B was then drawn up in a new mL Luer-Lok syringe,attached to the nitinol catheter and finally to the hand torque syringedelivery device which allowed controlled quantities of solutions Part Aand B to be delivered simultaneously.

[0079] Solutions Part A and B were slowly injected through thecatheters. Upon the two solutions contacting in the tip of themicrocatheter hydrogel formation was initiated. The resulting polymerexited the tip of the microcatheter in a string or thread like formequal in diameter to the internal diameter of the microcatheter.

EXAMPLE 2

[0080] The two pre-polymer solutions were formulated as follows. Eachsolution was individually weighed or dispensed in to a 20 mlscintillation vial furnished with a magnetic stirrer bar then stirreduntil homogeneous. The solutions were then allowed to stand to allow anyresulting air bubbles to dissipate. Part A: 30% Acrylamidefunctionalized PVA macromer 3.00 g Acryloxyethyl trimethylammoniumchloride (80%) 0.38 g Omnipaque 350 6.10 g 415 mM Hydrogen peroxide 500uL

[0081] Part B: 30% Acrylamide functionalized PVA macromer 0.67 gAcryloxyethyl trimethylammonium chloride (80%) 1.25 g Omnipaque 350 6.35g  83 mM Fe(II) lactate 1.50 g 415 mM Ascorbic acid 0.20 g

[0082] A similar delivery device was used as in Example 1. The outercatheter was a 2.5 Fr Renegade microcatheter (Boston Scientific, Target;length=150 cm). The inner catheter was a nitinol catheter (length 175cm, o.d. 0.012 inches) with a spiral cut tip. The mixing chamber wasabout 6 cm.

[0083] As in example 1, a hydrogel string having approximately thediameter of the delivery device outer catheter was extruded from thedevice.

[0084] Modifications and variations of the present invention will beapparent to those skilled in the art from the forgoing detaileddescription. All modifications and variations are intended to beencompassed by the following claims. All publications, patents, andpatent applications cited herein are hereby incorporated by reference intheir entirety.

What is claimed is:
 1. A method for forming a hydrogel string comprisingthe steps: providing a delivery device having a gelation chamber;providing a prepolymer composition that will form a hydrogel whenbrought into contact with a gelation initiator; contacting theprepolymer with the gelation initiator in the gelation chamber so thatit form a hydrogel in the gelation chamber; and extruding the hydrogelfrom the delivery device as a hydrogel string.
 2. The method of claim 1,wherein the delivery device is a catheter.
 3. The method of claim 2,wherein the delivery device is a multilumen catheter.
 4. The method ofclaim 1, wherein the delivery device is a catheter having at least twolumens and a gelation chamber at the distal end.
 5. The method of claim4, wherein the catheter is a coaxial catheter having an inner catheterand an outer catheter and the method further comprises the step of stepof sliding the inner catheter within the outer catheter to increase ordecrease the length of the gelation chamber.
 6. The method of claim 1,wherein the prepolymer composition comprises at least two solutions thatwill form a hydrogel when combined in the gelation chamber.
 7. Themethod of claim 1, wherein the hydrogel is extruded as prepolymercomposition is moved into the gelation chamber.
 8. The method of claim1, wherein the delivery device is a coaxial dual lumen catheter and theinner catheter is slidable within the outer catheter so that the degreeof formation of the hydrogel string as it exits the gelation chamber canbe altered as the inner catheter is slid towards the distal end of thegelation chamber.
 9. A hydrogel string formed by the method of claim 1.10. A hydrogel string formed by the method of claim
 5. 11. A hydrogelstring formed by the method of claim
 6. 12. A hydrogel string formed bythe method of claim 8.